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Reaction of methyl 2,3,4-tri-O-acetyl-1-O-(trichloroacetimidoyl)-α-D-glucopyranuronate with 3′-deoxy-3′-fluorothymidine in the presence of trimethylsilyl trifluoromethanesulfonate gave (2R,3R,4S,5S,6S)-2-(((2R,3S,5R)-3-fluoro-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate, which was hydrolysed to 3′-deoxy-3′-fluorothymidine-5′-glucuronide. Analysis of this reference standard by high performance liquid chromatography enabled the identification of [18F]3′-deoxy-3′-fluorothymidine-5′-glucuronide in blood samples from six human patients who had been administered [18F]3′-deoxy-3′-fluorothymidine.

The study is aimed at the analysis and identification of radiochemical and chemical impurities present in [18F]FLT synthesized by a simplified combination-column purification procedure, instead of the currently used HPLC purification. HPLC analysis of the final product showed an anionic radioactive byproduct, which was established as [18F]4-FBSA. The identity of the product was also confirmed by the radiofluorination of nosyl chloride. Mass spectrum analysis of both a decayed sample of [18F]FLT and fluorinated nosyl chloride showed a major peak at 242. We have also investigated the possible interference of this byproduct during PET-imaging in rabbits.

The role of the base in the synthesis of 3′-deoxy-3′-[18F]fluorothymidine, [18F]FLT, via nucleophilic substitution of the nosyl group with [18F]fluoride was investigated. The rate of 18F-incorporation into the molecule dramatically changed as a function of the precursor-to-base ratio. In the presence of excess base, the precursor was consumed by elimination before substitution was complete. When the precursor-to-base ratio was optimal, an overall [18F]FLT yield of 30–40% was achieved even if the precursor amount was as small as 8–13 mg.

A series of pro-nucleotide phosphoramidates and phosphorodiamidates of the antiviral lead compound 3′-deoxy-3′-fluorothymidine (FLT) have been designed and synthesized. In vitro antiretroviral and cytostatic studies revealed potent (sub-micromolar) inhibition of HIV-1 and HIV-2 replication, with retention of activity in thymidine kinase-negative cell models, as predicted by the ProTide concept.

Targeted molecular radiotherapy opens unprecedented opportunities to eradicate cancer cells with minimal irradiation of normal tissues. Described in this study are radioactive cyclosaligenyl monophosphates designed to deliver lethal doses of radiation to cancer cells. These compounds can be radiolabeled with SPECT- and PET-compatible radionuclides as well as radionuclides suitable for Auger electron therapies. This characteristic provides an avenue for the personalized and comprehensive treatment strategy that comprises diagnostic imaging to identify sites of disease, followed by the targeted molecular radiotherapy based on the imaging results. The developed radiosynthetic methods produce no-carrier-added products with high radiochemical yield and purity. The interaction of these compounds with their target, butyrylcholinesterase, depends on the stereochemistry around the P atom. IC(50) values are in the nanomolar range. In vitro studies indicate that radiation doses delivered to the cell nucleus are sufficient to kill cells of several difficult to treat malignancies including glioblastoma and ovarian and colorectal cancers.

Nucleoside triphosphate isosteres 5′-deoxy-5′-[[[[(4-methylphenyl)sulfonyl] amino] carbonyl] amino] thymidine (1), 5′-deoxy-5′-[[[[(4-chlorophenyl) sulfonyl] amino] carbonyl] amino] thymidine (2), 5-[[[[(3-methyl-benzyl) sulfonyl] amino] carbonyl] amino] thymidine (7), 3′,5′-dideoxy-3′-fluoro-5′-[[[[(4-methylphenyl) sulfonyl] amino] carbonyl] amino] thymidine (9) and 3′-deoxy-3′-fluoro-5′-O-[[[(4-methylphenyl) sulfonyl] amino] carbonyl] thymidine (10) have been synthesized from 5′-deoxy-5′-aminothymidine and 3′-deoxy-3′-fluorothymidine.

A convenient preparation of α- and β-anomers of 1,5-di-O-benzoyl-2,3-dideoxy-3-fluoro-D-erythro-pentofuranose is described. Each anomer is studied as the glycosylating agent in the reaction with bis-trimethylsilylated thymine in the presence of trimethylsilyl triflate. Under optimum conditions, 2',3'-dideoxy-3'-fluorothymidine (FLT) and its α-anomer are isolated in 64 and 25% yields, respectively

Inoculation of cynomolgus monkeys with simian immunodeficiency virus (SIVSM) results in an acute infection with circulating viral antigen. The time for appearance of the viral antigen peak was dependent on the dose of virus given, a reduced dose of virus resulting in a later peak. 3′-Fluorothymidine (FLT) was given at a dose of 3 × 5mg kg−1 day−1 starting 8 h before virus inoculation and then every 8 h for 10 days. In monkeys inoculated with 500–2500 infectious doses of SIVSM no significant effect of treatment with FLT was seen. When the amount of virus was reduced to 100 infectious doses or less, treatment with FLT resulted in a significant delay in the appearance of viral antigen. At an inoculum of 2–10 infectious doses per monkey, FLT treatment showed a prophylactic effect.

The 5-OH-protected methyl glycosides 2 and 3 were epimerized to give the corresponding epimers 6 and 7 via an oxidation-reduction procedure. Reaction of 6 with diethylamino-sulfur trifluoride (DAST) afforded the fluoro sugar 8, which was coupled with thymine to give 3′-deoxy-3′-fluorothymidine (12) after deprotection with saturated ammonia in methanol.

TPS125 Background: Neoadjuvant chemotherapy (NAC) prior to surgery provides enhanced options for locoregional management and has become an integral component of primary breast cancer management. Initial tumor response in patients receiving NAC is generally determined at therapy completion. This evaluation is determined by either the presence/absence of palpable tumor as a clinical response and/or presence/absence of invasive tumor cells in the breast and nodes as a pathological response. The ability to evaluate the effectiveness of neoadjuvant therapy early during treatment would be of significant importance. FDG PET imaging has been shown to be predictive of subsequent tumor response, but the tendency of FDG to accumulate in inflammatory tissues can complicate image interpretation. MRI changes have also been touted as predictors of response. Preliminary data suggest that early FLT PET is better able to predict response to therapy, as FLT uptake has been shown to correlate with cellular proliferation, and...

The use of methyl 5-0- tert -butyldiphenylsilyl-2-deoxy-α , β -D- threo -pentofuranoside, prepared from D-xylose,as a divergent intermediate for the synthesis of 3'-substituted-2',3'-dideoxynucleosides is illustrated by its conversion into 3'-azido-3'-deoxythymidine, 3'-deoxy-3'-fluorothymidine and 3'-cyano-3'-deoxythymidine.

Stereospecific synthesis of (−)-carba-3′-deoxy-3′-fluorothymidine (−)- 11 is reported from the protected (−)-carbocyclic 3′-epi-thymidine (−)- 7 using diethylaminosulfur trifluoride. Under the conditions used, extensive dehydration of the blocked precursor into 10 and formation of the 4′-fluoro analogue ( 9 ) were also observed. An attempted simplification of our methodology based on (+)-(1R, 5S)-2-oxabicyclo[3.3.0]oct-6-en-3-one failed, but a novel cyclopentane ( 2 ) ring expansion to tetrahydropyran ( 18 ) was discovered.

(−)-Carba-2′,3′-dideoxythymidine 5a and (−)-carba-2′,3′-dideoxy-3′-fluorothymidine 5b were, prepared from (±)- endo -5-norbornen-2-o1 using both enzymatic and chemical procedures.